Ellen Sandor, Stephan Meyers, and Janine Fron, (art)n
Dr. TJ O'Donnell
Ravi Kurumbail, Jennifer Pawlitz, Anna Stevens, Roderick Stegeman, James Gierse and William Stallings, Monsanto Company
Special thanks to Howard Stein, Hank Whittemore and Karen Sinsheimer.
Duratrans, Kodalith, Plexiglas
(art)n Virtual Visions: Three Decades of Collaboration, Brunnier Art Museum, Iowa State University, Ames, Iowa, October 29, 2002––January 5, 2003
Molecular Graphics Art Show, Reuben H. Fleet Space Theatre and Science Center, Balboa Park, San Diego, CA, December 2, 1998–January 15, 1999
Out of Sight: Imaging/Imagining Science, Santa Barbara Art Museum, Santa Barbara, CA, April 11-June 7 1998
Santa Barbara Museum of Art
Various Private Collectors
"Your Future Self" by Hank Whittemore
Skokie-based drugmaker Searle's headache gone
by Judith Graham, NEWS HOME Tribune Staff Writer
BUSINESS NEWS, The Chicago Tribune
Excerpt from Wednesday, January 14, 1998–Among them, drugs for arthritis represent a huge but highly fragmented segment of the pharmaceutical market that is expected to explode as the Baby Boomers pass through middle age.
An estimated 40 million Americans have arthritis, a condition that causes painful swelling around the joints and that costs an estimated $65 billion a year in medical bills, disability payments and lost time at work.
Drugs used to treat the condition, for which there is no known cure, include everything from aspirin and ibuprofen available over the counter, to prescription drugs that reduce inflammation, known as non-steroidal anti-inflammatory drugs (NSAIDs).
An estimated 30 million people worldwide take anti-inflammatory medications daily, often switching medications when complications develop or the drugs prove less effective than expected, according to various experts.
Searle has gradually built arthritis drugs into its largest single product category, led by Daypro (oxaprozin), the No. 2 anti-inflammatory prescription drug in the U.S. with worldwide sales of about $330 million a year, and Cytotec (misoprostol), the only arthritis drug currently available that prevents stomach ulcers, a common and dangerous side effect of existing therapies.
Cytotec's worldwide sales are close to $200 million. Now, Searle is rolling out a new drug for arthritis sufferers, Arthrotec, that combines both of those benefits, fighting inflammation and preventing complications at the same time. "It's a significant advance," said Dr. Jay Goldstein, a gastroenterologist at the University of Illinois at Chicago College of Medicine, noting that medical complications associated with existing therapies can be extremely serious.
Indeed, more than 75,000 people taking non-steroidal anti-inflammatory drugs, the most common type of arthritis medication, are hospitalized each year for serious side effects of the drugs such as bleeding, perforated ulcers or kidney
problems; about 7,600 of these patients die.
The problem is that there are good types of inflammation (essential to the functioning of the stomach and the kidneys) and bad (such as arthritic inflammation around the joints), and the non-steroidal drugs interfere with both over time. As a result, medical complications such as bleeding or stomach perforations often develop in patients taking the drug--yet four out of five people have no symptoms. Frequently "physicians underrecognize the problem" of medical complications from the drug therapy and undertreat it, Goldstein said.
Dr. Doyt Conn, medical director of the Atlanta-based Arthritis Foundation, cautioned that non-steroidal drugs ease the symptoms of arthritis but do not cure the condition. Too often, doctors treat the symptoms rather than diagnosing the disease early and trying to prevent it from getting worse.
Still, physicians should be receptive to the argument that an arthritis drug with a built-in prevention component is safer than therapies currently available, said Dr. Robert Katz, associate professor of medicine at Rush Medical College. "They're aware of the problems with current therapies and want an alternative," he said.
If so, Arthrotec could become a $400 million to $500 million-a-year drug, the largest in Searle's portfolio, in the next three to four years. It's already the top selling non-steroidal anti-inflammatory drug for arthritis in Canada, Sweden and Holland, No. 2 in the United Kingdom, and No. 3 in Germany.
But Searle isn't stopping there. It already has a successor to Arthrotec in the works, a drug known as Celecoxib, which analysts believe could help revolutionize arthritis treatment and generate annual sales in excess of a billion dollars.
Celecoxib is what's known as a COX-2 inhibitor, a new class of agent that selectively targets the bad type of inflammation that causes arthritis while not interfering with the good type of inflammation that allows the stomach and kidneys to function properly.
Searle has recently completed the last round of research on its COX-2 inhibitor, and it plans to submit a new drug application to the Food and Drug Administration by midyear. If all goes as planned, the company hopes to bring Celecoxib to market in 1999, becoming the first drug company to launch the medication and beating rival Merck & Co., which also has a COX-2 inhibitor under development.
With a characteristic push to remain on the cutting edge of scientific advances, however, Searle is also working on a second-generation COX-2 inhibitor. "We believe these products will help change the landscape of the arthritis market," chief operating officer Heller said.
Analyst Stover agrees. "These products have the potential to be bigger than any product Searle has today," he said. "Now, the question is how the company executes (its strategies) going forward."
The COX2 protein structure using cylinders to represent the alpha-helices which are connected by loops having less regular structure. The protein has three major domains, here colored green (the egf or epidermal growth factor domain), orange (the membrane domain) and red (the catalytic domain).
Embedded in the catalytic domain are a heme molecule (grey spheres) and a drug molecule acting to inhibit this enzyme. The drug is colored purple, with several atoms colored red (oxygen), blue (nitrogen) and yellow (sulphur). The drug is surrounded by a dot surface indicating how it might enter into the enzyme through the membrane domain of the protein. Finally, one of the tyrosine amino acids in the catalytic domain is shown between the heme and the inhibitor.
This tyrosine is crucial to the catalytic enzymatic activity of this protein.
The protein is known as COX2 or cyclo-oxygenase 2. Monsanto is developing drugs which inhbit this enzyme. These drugs act as anti-inflammatory drugs, like aspirin but without the gastro-intenstinal side-effects.
Some steroids, such as cortisone have been used as anti-inflammatory drugs, but have undesirable side effects. But new, selective COX2 inhibitors are not steroids and they do not have the gastro-intenstinal side-effects of older drugs such as aspirin, ibuprofen or naproxen.
These drugs are new members of an important class of drugs called non-steroidal anti-inflammatory drugs, or NSAIDs.
All NSAIDs have analgesic, anti-inflammatory and antipyretic activity. They share a joint mechanism of action–blockage of the enzyme cyclo-oxygenase which is involved in the metabolism of arachidonic acid to prostaglandins. Arachidonic acid is released from membrane phospholipids in response to inflammatory stimuli.
The prostaglandins perpetuate the inflammatory response. NSAIDs also affect other inflammatory processes.
Shown here is the crystal structure of Celecoxib bound to cyclooxygenase-2 (COX-2). Celecoxib is a selective inhibitor of COX-2 from Searle/Monsanto that is undergoing late stage clinical trials for osteo-arthritis and rheumatoid arthritis. Pre-clinical and early clinical studies have demonstrated that celecoxib is efficacious in reducing inflammation without the typical side effects characteristic of existing nonsteroidal anti-inflammatory drugs. It is bound in the cyclooxygenase active site of COX-2.